1. Classification of antifungal drugs
   • Polyenes, azoles, echinocandins, allylamines, antimetabolites, mitosis inhibitors, and topical agents.
2. Itraconazole
   • Mechanism of action, spectrum and therapeutic uses, pharmacokinetics, adverse effects, interactions, precautions.
3. Ketoconazole
   • Mechanism, current limited role in therapy, endocrine effects, hepatotoxicity, interactions, adverse effects.
4. Griseofulvin
   • Mechanism involving fungal mitosis, dermatophyte-only activity, clinical uses in tinea infections, adverse effects and interactions.
5. Amphotericin B
   • Mechanism, formulations, indications in severe systemic mycoses, infusion reactions, nephrotoxicity, electrolyte abnormalities, and lipid formulations.
6. Topical antifungals
   • Azoles, allylamines, ciclopirox, amorolfine, nystatin, tolnaftate, and their site-specific clinical uses.

1. Classification of antifungal drugs
2. Itraconazole: mechanism, uses, adverse effects, interactions
3. Ketoconazole: mechanism, uses, adverse effects, interactions
4. Griseofulvin: short note
5. Amphotericin B: short note
6. Topical antifungals and clinical uses

1. Classification of antifungal drugs
2. Itraconazole
3. Ketoconazole
4. Griseofulvin
5. Amphotericin B
6. Topical antifungals

1. Classification of Antifungal Drugs

Introduction

• Ergosterol in fungal cell membrane
• Ergosterol synthesis
• Fungal cell wall beta-(1,3)-D-glucan synthesis
• Nucleic-acid synthesis
• Mitotic spindle function

Classification according to mechanism of action

A. Drugs that act on fungal cell membrane

1. Polyene antibiotics

Drugs

1. Amphotericin B
2. Nystatin
3. Natamycin (pimaricin)

Mechanism

• Polyenes bind to ergosterol in the fungal cell membrane.
• They create pores in the membrane.
• Intracellular ions and cell constituents leak out.
• This causes fungal cell death.

Important points

• Usually fungicidal.
• Amphotericin B is used mainly in severe, life-threatening systemic fungal infections.
• Nystatin is used locally for candidiasis and is not used systemically due to toxicity and poor absorption.
• Natamycin is used mainly in fungal keratitis.

B. Drugs inhibiting ergosterol synthesis

2. Azole antifungals

Mechanism common to all azoles

Effects

• Decreased ergosterol formation
• Defective fungal cell membrane
• Increased membrane permeability
• Inhibition of fungal growth

Classification of azoles

A. Imidazoles

Mainly topical imidazoles

• Clotrimazole
• Miconazole
• Econazole
• Tioconazole
• Isoconazole
• Oxiconazole
• Sulconazole
• Sertaconazole
• Luliconazole
• Bifonazole
• Eberconazole
• Fenticonazole

Systemic imidazole

• Ketoconazole

B. Triazoles

• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Isavuconazole

• Fluconazole: candidiasis, cryptococcosis
• Itraconazole: dermatophytosis, onychomycosis, histoplasmosis, blastomycosis, sporotrichosis
• Voriconazole: invasive aspergillosis
• Posaconazole: prophylaxis and treatment of selected invasive mould infections
• Isavuconazole: invasive aspergillosis and mucormycosis

3. Allylamines and related drugs

Drugs

• Terbinafine
• Naftifine
• Butenafine

Mechanism

• Inhibit squalene epoxidase, an early enzyme in ergosterol synthesis.
• This causes:
  • Decreased ergosterol synthesis
  • Accumulation of toxic squalene within fungal cells

Uses

• Dermatophyte infections
• Tinea pedis
• Tinea corporis
• Tinea cruris
• Tinea capitis
• Onychomycosis

Important point

• Terbinafine is especially effective against dermatophytes and is commonly used orally for onychomycosis.

4. Morpholine derivative

Drug

• Amorolfine

Mechanism

• Inhibits two enzymes in ergosterol synthesis:
  • Delta-14 reductase
  • Delta-7,8-isomerase

Use

• Mainly topical treatment of onychomycosis.

C. Drugs acting on fungal cell wall

5. Echinocandins

Drugs

• Caspofungin
• Micafungin
• Anidulafungin
• Rezafungin

Mechanism

• Inhibit beta-(1,3)-D-glucan synthase.
• Beta-(1,3)-D-glucan is an essential component of the fungal cell wall.
• Inhibition leads to cell-wall weakness, osmotic instability, and fungal cell lysis.

Antifungal activity

• Fungicidal against Candida
• Fungistatic against Aspergillus

Uses

• Invasive candidiasis and candidemia
• Esophageal candidiasis
• Invasive aspergillosis, usually as salvage or combination therapy in selected situations
• Empirical treatment in febrile neutropenia, depending on the clinical setting

Important points

• Given intravenously.
• Relatively fewer renal adverse effects and drug interactions than amphotericin B or many azoles.
• They have little or no activity against Cryptococcus and Mucorales.

D. Drugs inhibiting nucleic-acid synthesis

6. Antimetabolite

Drug

• Flucytosine or 5-fluorocytosine

Mechanism

• Flucytosine enters fungal cells through cytosine permease.
• It is converted within fungal cells to 5-fluorouracil (5-FU).
• 5-FU inhibits thymidylate synthase, thus inhibiting DNA synthesis.
• Its metabolites also interfere with RNA synthesis and protein synthesis.

Uses

• Used only in combination, because resistance develops rapidly with monotherapy.
• Combined with amphotericin B for:
  • Cryptococcal meningitis
  • Severe cryptococcosis
  • Selected severe Candida infections

Adverse effects

• Bone marrow suppression
• Leukopenia
• Thrombocytopenia
• Gastrointestinal upset
• Hepatotoxicity

E. Drug inhibiting mitosis

7. Griseofulvin

Mechanism

• Binds fungal microtubules and disrupts formation of the mitotic spindle.
• Arrests fungal cell division at metaphase.
• Deposits in newly formed keratin, making it resistant to dermatophyte invasion.

Spectrum

• Trichophyton
• Microsporum
• Epidermophyton

Uses

• Tinea capitis
• Tinea corporis
• Tinea cruris
• Tinea pedis
• Dermatophytic nail infection, though terbinafine is generally preferred now

Important point

F. Miscellaneous topical antifungals

8. Ciclopirox olamine

Mechanism

• Chelates polyvalent metal ions such as Fe³⁺ and Al³⁺.
• This inhibits fungal metal-dependent enzymes and disrupts cellular metabolism.

Uses

• Dermatophytosis
• Cutaneous candidiasis
• Pityriasis versicolor
• Seborrheic dermatitis
• Mild to moderate onychomycosis as nail lacquer

9. Tolnaftate

Mechanism

• Exact mechanism is not fully established.
• It interferes with fungal growth, probably through effects on squalene epoxidase or membrane function.

Uses

• Topical treatment of dermatophyte infections:
  • Tinea pedis
  • Tinea corporis
  • Tinea cruris

Limitation

• Not effective against Candida.

10. Undecylenic acid

Uses

• Topical treatment of mild dermatophyte infections, especially tinea pedis.

11. Selenium sulfide

Uses

• Topical lotion or shampoo for:
  • Pityriasis versicolor
  • Seborrheic dermatitis
  • Dandruff

12. Potassium iodide

Uses

• Saturated solution of potassium iodide may be used in cutaneous and lymphocutaneous sporotrichosis.

Classification according to route of administration

1. Topical antifungal drugs

• Clotrimazole
• Miconazole
• Econazole
• Ketoconazole
• Luliconazole
• Sertaconazole
• Terbinafine
• Naftifine
• Butenafine
• Tolnaftate
• Ciclopirox
• Amorolfine
• Nystatin
• Natamycin
• Selenium sulfide

2. Oral antifungal drugs

• Fluconazole
• Itraconazole
• Terbinafine
• Griseofulvin
• Flucytosine
• Ketoconazole, now rarely used as an oral antifungal because of toxicity
• Voriconazole
• Posaconazole
• Isavuconazole

3. Parenteral antifungal drugs

• Amphotericin B and lipid formulations
• Caspofungin
• Micafungin
• Anidulafungin
• Rezafungin
• Fluconazole
• Voriconazole
• Posaconazole
• Isavuconazole
• Flucytosine is generally oral, but may be used in combination for severe systemic disease

One-line revision table

High-yield exam points

• Amphotericin B and nystatin bind fungal ergosterol.
• Azoles inhibit 14-alpha-demethylase and block ergosterol synthesis.
• Terbinafine inhibits squalene epoxidase.
• Echinocandins inhibit fungal cell-wall beta-(1,3)-D-glucan synthesis.
• Flucytosine inhibits fungal nucleic-acid synthesis and should not be used alone because resistance develops rapidly.
• Griseofulvin inhibits mitosis and is effective only against dermatophytes.
• Topical therapy is generally suitable for localized superficial fungal infection; hair, nail, extensive, refractory, or invasive disease often requires systemic therapy.

Itraconazole

Class

• Triazole antifungal
• Broad-spectrum systemic antifungal.
• Available as oral capsules, oral solution, and intravenous formulation in some settings.

Mechanism of action

Sequence

1. Normally, fungal cells convert lanosterol to ergosterol through 14-alpha-demethylase.
2. Itraconazole blocks this enzyme.
3. Ergosterol synthesis falls.
4. Abnormal sterols accumulate in the fungal cell membrane.
5. The membrane becomes structurally and functionally defective, inhibiting fungal growth.

Final effect

• Usually fungistatic against many yeasts.
• Can be fungicidal against Aspergillus species.

Additional pharmacological points

• Itraconazole inhibits human CYP3A4 and P-glycoprotein, so clinically important drug interactions are common.
• Capsule absorption is best with food and requires an acidic gastric environment.
• Oral solution is better absorbed when taken fasting.
• Antacids, H2 blockers, and proton-pump inhibitors can reduce absorption, particularly of capsules.

Therapeutic uses

1. Dermatophytosis

• Tinea corporis
• Tinea cruris
• Tinea pedis
• Tinea manuum
• Tinea faciei

2. Onychomycosis

• Fungal infection of finger or toe nails, especially dermatophyte onychomycosis.
• It achieves high concentrations in keratinized tissues such as skin and nails.

3. Tinea versicolor

• Due to Malassezia species.
• Used when disease is extensive or recurrent and topical therapy is impractical or has failed.

4. Candidiasis

• Oral candidiasis
• Esophageal candidiasis
• Vulvovaginal candidiasis
• Chronic mucocutaneous candidiasis

5. Aspergillosis

• Used for invasive aspergillosis when appropriate.
• Also used in chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis in selected patients.
• It has activity against Aspergillus and was historically an important oral option.

6. Endemic systemic mycoses

• Histoplasmosis
  • Mild to moderate disease
  • Step-down treatment after initial amphotericin B in severe disease
  • Maintenance treatment in selected disseminated disease
• Blastomycosis
• Sporotrichosis
  • Especially lymphocutaneous and osteoarticular sporotrichosis
• Paracoccidioidomycosis
• Coccidioidomycosis, in selected patients

7. Phaeohyphomycosis and other rare mould infections

Adverse effects

Common adverse effects

Gastrointestinal

• Nausea
• Vomiting
• Dyspepsia
• Abdominal pain
• Diarrhea or constipation

Central nervous system

• Headache
• Dizziness
• Fatigue

Skin and hypersensitivity

• Rash
• Pruritus
• Urticaria
• Rarely angioedema, anaphylaxis, or Stevens-Johnson syndrome

Important adverse effects

1. Hepatotoxicity

• Elevation of liver enzymes
• Hepatitis
• Cholestatic jaundice
• Rarely severe hepatic failure

2. Negative inotropic effect and congestive heart failure

• Itraconazole can reduce myocardial contractility.
• It may cause or worsen:
  • Peripheral edema
  • Pulmonary edema
  • Congestive heart failure

3. Drug interactions

• Statins, particularly simvastatin and lovastatin
• Calcium-channel blockers
• Benzodiazepines, especially oral midazolam and triazolam
• Some antiarrhythmics
• Immunosuppressants, such as cyclosporine and tacrolimus
• Certain anticoagulants
• Some antiepileptic and antineoplastic drugs

• Excessive sedation
• Myopathy or rhabdomyolysis
• Hypotension
• QT prolongation and dangerous arrhythmias
• Increased nephrotoxicity with calcineurin inhibitors

4. Hypokalemia and edema

• Peripheral edema may occur.
• Hypokalemia has been reported, particularly with systemic treatment and interacting medicines.

5. Peripheral neuropathy

• Rarely, paresthesia or peripheral neuropathy may develop.

Contraindications and precautions

Avoid or use with great caution in

• Congestive heart failure or ventricular dysfunction
• Active liver disease or previous severe drug-induced liver injury
• Pregnancy, unless benefits clearly outweigh fetal risk
• Patients receiving medicines with serious CYP3A4-mediated interactions

Monitoring during prolonged therapy

• Clinical response
• Liver function tests
• Signs of edema or heart failure
• Drug-interaction review
• Serum itraconazole concentration in severe systemic infection, suspected poor absorption, or treatment failure

Exam summary

Ketoconazole

Class

• Imidazole antifungal
• Available mainly as topical cream, shampoo, foam, gel, and sometimes oral formulations.
• Oral ketoconazole is now rarely used for fungal infections because safer alternatives are available and it can cause severe toxicity.

Mechanism of action

Sequence of action

1. Normally, fungal lanosterol is converted to ergosterol.
2. Ketoconazole blocks 14-alpha-demethylase.
3. Ergosterol synthesis decreases.
4. Abnormal sterols accumulate in the fungal cell membrane.
5. Fungal membrane structure and function are impaired, inhibiting fungal growth.

Final effect

• Mainly fungistatic
• May become fungicidal at high local concentrations.

Additional endocrine action

• Cortisol
• Testosterone
• Aldosterone, to a lesser degree
• Other adrenal and gonadal steroids

Therapeutic uses

A. Topical uses

1. Dermatophytosis

• Tinea corporis
• Tinea cruris
• Tinea pedis
• Tinea manuum
• Tinea faciei

2. Pityriasis versicolor

• Caused by Malassezia species.
• Ketoconazole shampoo or cream may be used.

3. Seborrheic dermatitis and dandruff

• Ketoconazole shampoo is effective because Malassezia contributes to these conditions.
• It also has some local anti-inflammatory effect.

4. Cutaneous candidiasis

• Intertrigo
• Diaper candidiasis
• Other localized skin infections caused by Candida

5. Vaginal candidiasis

• Some local vaginal preparations may be used, although other azoles are often preferred.

B. Oral uses

Historical antifungal uses

• Extensive dermatophytosis
• Chronic mucocutaneous candidiasis
• Pityriasis versicolor
• Paracoccidioidomycosis
• Histoplasmosis
• Blastomycosis
• Coccidioidomycosis

Endocrine use

• It may be used under specialist care to reduce cortisol production in Cushing syndrome, especially when other options are unsuitable.
• Hydrocortisone may be coadministered in a "block-and-replace" approach because ketoconazole can suppress adrenal steroid synthesis.

Adverse effects

1. Gastrointestinal effects

• Nausea
• Vomiting
• Abdominal discomfort
• Dyspepsia
• Diarrhea

2. Hepatotoxicity

• Elevated liver enzymes
• Hepatitis
• Cholestatic jaundice
• Severe liver failure
• Rarely fatal hepatic injury or liver failure requiring transplantation

3. Endocrine adverse effects

In males

• Decreased testosterone production
• Gynecomastia
• Reduced libido
• Erectile dysfunction
• Oligospermia or reduced sperm count
• Infertility with prolonged use

In females

• Menstrual irregularities

Adrenal effects

• Reduced cortisol synthesis
• Adrenal insufficiency, particularly at higher doses
• Weakness, hypotension, fatigue, nausea, and hypoglycemia may occur in significant adrenal suppression

4. Drug interactions

• Warfarin and other anticoagulants
• Cyclosporine and tacrolimus
• Some statins, especially simvastatin and lovastatin
• Certain calcium-channel blockers
• Benzodiazepines, especially oral midazolam and triazolam
• Some antiarrhythmics
• Certain antihistamines and antipsychotic drugs
• Some antiretroviral and anticancer drugs

Consequences

• QT prolongation
• Torsades de pointes and serious arrhythmias
• Excessive sedation
• Hypotension
• Rhabdomyolysis with interacting statins
• Enhanced nephrotoxicity with calcineurin inhibitors

5. Reduced absorption with high gastric pH

• Antacids
• H2 blockers
• Proton-pump inhibitors
• Achlorhydria

6. Hypersensitivity and dermatological reactions

• Rash
• Pruritus
• Urticaria
• Rarely severe cutaneous reactions

Topical adverse effects

• Burning
• Stinging
• Itching
• Erythema
• Local irritation
• Contact dermatitis

Contraindications and precautions

Avoid oral ketoconazole in

• Liver disease
• Pregnancy unless there is a compelling specialist indication
• Patients on contraindicated CYP3A4 substrates
• Patients at risk of QT prolongation
• Patients with adrenal insufficiency, unless specifically treated and monitored

Monitoring if systemic use is essential

• Liver function tests
• Clinical features of hepatic injury
• Serum cortisol or symptoms of adrenal suppression where relevant
• Concomitant medicines for CYP3A4 interactions
• ECG risk and electrolyte status in patients at risk of arrhythmia

Exam summary